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Adding pegylated interferon to
entecavir (Baraclude) led to greater
hepatitis B virus (HBV) viral load decline and higher likelihood of serological
response in people with HBeAg-positive chronic hepatitis B, as did added
interferon after long-term nucleoside therapy, but adding interferon after only
a short course of antivirals did not improve response, according to a set of
studies presented at the 49th Annual Meeting of the European Association for
the Study of the Liver (EASL) last week in
London.

Antiviral therapy for hepatitis B
generally does a good job of suppressing HBV DNA or viral load, but serological
response – including hepatitis B 'e' antigen (HBeAg) and surface antigen
(HBsAg) loss or seroconversion – is less common. Hepatitis B surface antibody
seroconversion, considered closest to a cure, is rare in people with chronic
HBV infection. Some past research indicates that adding interferon increases
the likelihood of antigen loss or seroconversion, but data have been
inconsistent.

"Nucleoside analogue antivirals, which
interfere with the HBV lifecycle, are standard treatment for chronic hepatitis
B," explained EASL Education Councilor Cihan Yurdaydin of the University of Ankara at a press conference summarising
the study findings. "Because only a minority of chronic hepatitis B
patients achieve HBsAg loss with entecavir, treatment is indefinite for the
majority of these patients. Interferon, which has long been the mainstay of
hepatitis C treatment, is known to stimulate the natural immune response
against viral infections. This synergistic effect should theoretically
contribute to improved outcomes for hepatitis B as well."

Entecavir + pegylated interferon

Willem Pieter Brouwer of Erasmus University Medical Centre in Rotterdam presented findings from the ARES
study, a randomised controlled trial comparing long-term treatments for people
with HBeAg-positive chronic hepatitis B.

This multinational analysis included 175
participants in Europe, Turkey
and China.
About 70% were men, 60% were Asian, 40% were Caucasian and the mean age was
approximately 32 years; 5% had liver cirrhosis at baseline.

All participants started treatment with
the nucleoside analogue antiviral entecavir. After 24 weeks they were randomly
assigned (1:1) to either continue on entecavir monotherapy or add pegylated
interferon alfa-2a. After 48 weeks of treatment, responders continued on
entecavir alone through week 72, while non-responders continued on entecavir
monotherapy through week 96.

The researchers looked at a combined
response endpoint of undetectable HBV DNA (<200 IU/mL) and HBeAg loss, as
well as durability of responses over time.

At 48 weeks, 19% of study participants who added
pegylated interferon reached the combined response endpoint, compared with 19%
treated with entecavir monotherapy. This difference did not reach statistical
significance, but adding interferon was associated with nearly 5-fold higher
likelihood of response in a multivariate analysis (odds ratio 4.78).

Looking at secondary endpoints, adding pegylated
interferon led to significantly greater declines in HBeAg and HBsAg levels,
while the difference in HBV DNA reductions did not reach statistical
significance. Only one person experienced HBs
antibody seroconversion.

Among participants who continued treatment through 96
weeks, those treated with entecavir plus interferon were numerically more
likely than those receiving entecavir monotherapy to experience HBeAg loss (31
vs 20%), HBsAg <1000 IU/mL (26 vs 14%) and the combined undetectable viral
load/HBeAg seroconversion endpoint (24 vs 11%), though only the last comparison
reached statistical significance.

Looking at sustained or off-treatment response among
people who stopped entecavir at week 72, those in the pegylated
interferon/entecavir group were more likely to have sustained HBeAg loss (64 vs
25%), sustained undetectable viral load/HBeAg seroconversion (69 vs 25%) and a
triple endpoint of low viral load (<2000 IU/mL), HBeAg loss and normal ALT
(79 vs 25%), with the latter two comparisons being statistically significant.

Combination therapy was described as safe and well-tolerated.
There were eight severe adverse events, including three ALT flares and one case
of severe neutropenia. Grade 3 neutropenia occurred in 28% and leukopenia in 9%
of participants taking pegylated interferon, but no one taking entecavir alone.

"In order to be able to stop entecavir [or
other nucleoside/nucleotide analogue treatment], immune control is needed, and
this study has shown that this may be achieved with peginterferon add-on,"
Yurdaydin explained.

Sequential therapy

In a related study, Wenhong Zhangof Fudan
University in Shanghai and colleagues looked at sequential
combination therapy with nucleoside analogues and pegylated interferon in people
with HBeAg-positive chronic hepatitis B who had already taken long-term
nucleosides.

This retrospective analysis included 192 people
with chronic hepatitis B who had been exposed to nucleoside analogues for at
least two years without HBeAg loss or seroconversion. 109 participants
continued on nucleoside monotherapy, while 83 received pegylated interferon and
nucleosides for a further 48 weeks. They were then followed for 24 weeks
post-treatment.

In this study, 60% of patients receiving
combination therapy reached a composite endpoint of HBeAg loss and HBV DNA
<2000 IU/ml, compared with only 14% in the nucleoside monotherapy arm. In
addition, 28% in the combination arm achieved HBsAg loss, compared with none in
the monotherapy arm.

The researchers also found that a baseline
HBsAg level below 1000 IU/ml was a good cut-off for predicting treatment
response. 100% of patients with <1000 IU/ml at baseline achieved the
composite response endpoint and 91% (all but one) achieved HBsAg loss, compared
with 54% and 18%, respectively, among people with >1000 IU/ml. HBsAg
levels at weeks 12 and 24 were strongly predictive of treatment response in the
combination therapy group. However, people who had an HBsAg decline of at
least 0.5 log at week 12 or 1.5 log at week 24 still had a chance of
responding.

"Sequential combination therapy of
[nucleoside analogues] and pegylated interferon effectively resulted in high
rates of complete response and HBsAg loss in patients with prior long-term
exposure to [nucleoside analogues]," the researchers concluded. "This
therapy can be guided by baseline level and dynamic on-treatment pattern of
HBsAg."

Brief antiviral therapy

A third study, however, did not see a
benefit of pegylated interferon following a short course of nucleoside/nucleotide
analogues.

Presented by Wei-Wen Su from Changhua Christian Hospital,
the NEED trial included 280 people with HBeAg-positive chronic hepatitis B in Taiwan. About
70% were men and the mean age was 38 years. About 60% were treatment-naive, 20%
had previously used interferon and 30% had previously used
nucleoside/nucleotide analogues.

Participants in this double-blind trial
were randomly assigned (1:1:1) to receive entecavir, adefovir (Hepsera) or placebo for six weeks.
Starting at week 4, they added pegylated interferon and stayed on triple
therapy for two weeks, then continued on interferon alone through week 52.

At 52 weeks, the rate of HBeAg
seroconversion was numerically higher in the pegylated interferon monotherapy
arm (27%) than in the groups that received short-term entecavir or adefovir
(22% and 21%, respectively), but the differences were not statistically significant.

After a further 24 weeks of off-treatment
follow-up, HBeAg seroconversion rates were 36%, 28% and 23% – again not
significant differences (though the pegylated interferon vs adefovir comparison
came close to significance).

HBV DNA levels, however, declined significantly more
in the entecavir and adefovir arms than in the pegylated interferon monotherapy
arm; entecavir also reduced viral load significantly more than adefovir.

Treatment was again described as generally well-tolerated.
Approximately 10% of participants experienced serious adverse events, but only
seven people withdrew early due to adverse events. The most common side-effects
were hair loss, headache, fever and muscle aches.

"This kind of sequential combination
strategy does not increase the HBeAg seroconversion rate compared to pegylated
interferon alfa-2a monotherapy at the end of treatment or at 24 weeks,"
the investigators concluded. "A strategy of initial combination with
[nucleoside/nucleotide analogues] for a longer treatment duration to achieve a
lower HBV DNA level before starting pegylated interferon requires further
study."

Su explained that the researchers
hypothesized that by not fully suppressing HBV viral load before starting
pegylated interferon, the residual virus would give interferon-stimulated
immune responses something to work on, but this strategy proved ineffective.

Reporters at the press conference
questioned the claim that pegylated interferon is 'well tolerated', given the
well-known difficult side-effects
seen among people taking the treatment for hepatitis C.

"If a disease is more difficult, the side-effect
threshold goes up," Yurdaydin explained. "In hepatitis C we now have
the luxury of getting rid of pegylated interferon. If we had the luxury in
hepatitis B, we would do it too."

He noted that the cost of ongoing
nucleoside/nucleotide analogue therapy is often prohibitive, so any way to
shorten treatment duration is important. "Together, these ground-breaking
data will go a long way to influencing future chronic hepatitis B treatment
guidelines," he predicted.

Li G et al. Sequential combination therapy with nucs and
peg-INF in HBeAg positive CHB patients with prior exposure to long-term of nucs. 49th Annual Meeting of the European
Association for the Study of the Liver, abstract O117, London, 2014.

European Association for the Study of the Liver Three
new studies help clarify optimal use of combination therapy with peginterferon
and nucleoside analogues in patients with chronic hepatitis B. Press release. April 12, 2014.

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NAM’s information is intended to support, rather than replace, consultation with a healthcare professional. Talk to your doctor or another member
of your healthcare team for advice tailored to your situation.